bioRxiv Subject Collection: Neuroscience's Journal

ROSMAP-Compass: A data-harmonised, AI-ready atlas of 22 million single nuclei from the ROSMAP cohort
The Religious Orders Study and Memory and Aging Project (ROSMAP) cohort has generated the world's most comprehensive single-cell transcriptomic resource for Alzheimer's disease research. Naturally, in a project spanning multiple years with dozens of research groups involved, the resulting data landscape shows fragmentation across sequencing chemistries, protocols, and pipelines. This presents both a challenge and a unique opportunity for harmonized, collaborative analysis. Following an early data integration strategy and complete realignment of all single nucleus RNA sequencing data, we generated a fully harmonized resource: ROSMAP-Compass, comprising more than 22 million high-quality nuclei from 2,058 donors in multiple brain regions from the ROSMAP and Neuro Psychiatric Symptoms (NPS-AD) cohorts. Through systematic curation and unified reprocessing, we addressed substantial technical challenges including chemistry-specific biases, cross-study batch effects, and sample redundancies across multiple studies spanning different time periods and research groups. ROSMAP-Compass demonstrates the critical importance of systematic data harmonization when integrating large-scale single-cell datasets from multiple sources. By combining open science principles with cutting-edge AI integration, we provide both a critical resource for understanding Alzheimer's disease heterogeneity and a blueprint for making complex biomedical data accessible to the global research community. The full resource, interactive web portal, and LLM compatible API are freely available, empowering researchers worldwide to accelerate discovery in neurodegenerative diseases.

Obsessive-Compulsive Tendencies Shift the Balance Between Competitive Neurocognitive Processes
Theoretical models of Obsessive-Compulsive Disorder (OCD) propose that its symptoms stem from an imbalance between habitual and goal-directed processes, marked by a bias toward habitual behavior and deficits in goal-directed control. While much of the existing research has focused on reward-based learning, the contribution of reward-independent learning processes to this imbalance remains unclear. To address this gap, the present study investigated the interaction between statistical learning (SL), a form of reward-free learning, and cognitive flexibility, a key goal-directed function, in a non-clinical population. By adopting a dimensional approach to obsessive-compulsive (OC) tendencies, this work aims to overcome the limitations of categorical diagnoses and better capture the continuous, nuanced variability of symptoms, while clarifying how specific neurocognitive processes relate to OC tendencies. A total of 402 participants from the non-clinical population completed an online study involving the Alternating Serial Reaction Time (ASRT) task to assess SL and a Card Sorting Task to measure cognitive flexibility. Our findings revealed a competitive relationship between SL and cognitive flexibility. Critically, this inverse association weakened as OC tendencies increased, suggesting that even at non-clinical levels, OC tendencies may interfere with the typical interplay between automatic and goal-directed processes. Notably, SL performance remained intact, and the observed effects were not attributable to reward sensitivity, as learning occurred without external feedback. These findings emphasize the value of examining non-clinical OC tendencies and highlight the importance of investigating neurocognitive system interactions, rather than isolated functions, in advancing our understanding of OCD.

A unified derivative-like dopaminergic computation across valences
Dopamine activity in the brain affects decision-making and adaptive behaviors. A wealth of studies indicate that dopamine activity encodes discrepancy between actual and predicted reward, leading to the reward prediction error (RPE) hypothesis. Specifically, it has been claimed that mesolimbic dopamine activity conforms to temporal-difference reward prediction error (TD RPE), a teaching signal in machine learning algorithms. Recently, there is growing evidence suggesting that dopamine is also involved in learning during aversive situations. However, the fundamental computation of dopamine activity in aversive situations is still unknown. A plausible but untested hypothesis is that dopamine activity in aversive situations also encodes TD RPE. Here, we tested this hypothesis by using mice in virtual reality. Mice were trained to avoid electrical tail shocks by running out of a virtual shock zone. Using probe conditions with speed manipulation or teleportation, we revealed that the dopamine signal in the ventral striatum follows the temporal derivative form of a value function. Delivering a reward at the end of the track enabled us to observe the integration of aversion and reward in a derivative form. Moreover, the value functions unbiasedly estimated from the recorded signal is consistent with the initial hypothetical form, with a realistic reflection of a received shock distribution. Taken together, our results show that mesolimbic dopamine activity can operate as a unified teaching signal in natural situations with positive and negative valences.

Unveiling the neuro-vascular interplay in the skeletal muscle in health, injury and disease
Neuromuscular junctions (NMJs) are complex multicellular structures that convey motor neuron-induced responses in the skeletal muscle. Their cellular composition is well characterized, but interactions between the different cell types and with the surrounding microenvironment remain underexplored. Here, by using a panel of newly discovered mouse cell lineage markers, single-cell RNA sequencing analyses and iDisco tissue clarification, we demonstrate the existence of contacts between adjacent NMJs through their kranocytes, assembling kranocyte network-like structures within the muscle interstitium, which is essential for regulating blood flow and supporting muscle regeneration. Indeed, kranocytes do contact with the surrounding microvasculature as well, both of them uncovering a previously unexplored, expansive interactive system. Moreover, unlike the robustness shown by their counterparts, the terminal Schwann cells, we strikingly observed that kranocytes rapidly detected stressful conditions, leading to structural changes and even the loss of their connections in response to acute damage, such as muscle injury or neuromuscular disease-induced denervation. Therefore, we propose kranocytes as the interactive sensory platforms of the NMJs, working in a perpendicular axis of nerve-transmission, as key NMJ-connectors by, interconnecting adjacent NMJs and interacting with the microvasculature and the microenvironment, and also as NMJ-sensors by detecting microenvironmental inputs. Together, our data postulate kranocytes as triple connectors of the nervous, musculoskeletal and vascular systems.

Interval Timing is altered in male Nrxn1+/- mice: A Model of Autism Spectrum Disorder
Autism spectrum disorder (ASD) is characterised by impaired social interactions and communication and increased repetitive and stereotypical behaviour. Neuroimaging shows functional abnormalities in brain areas involved in temporal processing of autistic individuals, and autistic individuals show deficits in interval timing. Neurexin (NRXN) mutations have been identified in a wide variety of neuropsychiatric disorders, including ASD, and Nrxn1+/- mice possess a mutation that disrupts the , {beta}, and {gamma} isoforms of Nrxn1, a gene involved in synapse structure. We investigated the interval timing abilities of the Nrxn1+/- mouse model of ASD in the peak interval procedure using a 15-second target interval and compared their performance with that of Nrxn1+/+ and Nrxn1{Delta}S5/- rescue mice. Two-month-old male Nrxn1+/+ (C57BL/6J), Nrxn1+/-, and Nrxn1{Delta}S5/-, mice were trained to obtain sucrose liquid rewards 15s after the onset of a discriminative stimulus (discrete fixed-interval training), and their timing responses were tested in non-reinforced probe trials. Our analysis of responses in individual trials revealed that Nrxn1+/- mice had overall earlier timing responses. This difference was manifested as earlier termination of responding in terms of the response curves. These findings are consistent with leftward shifts observed with experimental animal models of ASD. In conclusion, we believe that these results are indicative of a biased long-term memory in the Nrxn1+/- mouse model of ASD and may capture the timing deficit observed in autistic individuals. Lay Summary: Neurexins help nerve cells connect and communicate with each other, and changes in these genes are often seen in people with autism. Mice with a change in their neurexin 1 gene, called Nrxn1+/- mice, show autism-like behaviours. In a test that involves judging time, these mice respond early, similar to some people with autism. This study helps develop our understanding of how interval timing is affected in ASD.

CD11b Activation Reduces Myeloid Brain Infiltration and Mitigates Synucleinopathy in a Model of Parkinson's Disease
The pathology of Parkinson's disease is defined by -synuclein (-syn) aggregation into neuronal Lewy bodies, which may lead to chronic neuroinflammation and dopaminergic neurodegeneration. Misfolded -syn activates Toll-like receptor signaling in microglia, leading to downstream activation of NF-{kappa}B and subsequent release of pro-inflammatory cytokines. These cytokines recruit pro-inflammatory myeloid cells from circulation, thereby amplifying neuroinflammation. Thus, reducing microglial activation and myeloid cell infiltration has the potential to reduce neuroinflammation and PD pathology. Here, we investigated a targeted immunomodulatory strategy using LA1, a novel, small-molecule agonist of CD11b, a {beta}2 integrin receptor highly and selectively expressed on myeloid cells and microglia. CD11b has key roles in cell adhesion, migration, and phagocytosis. Previous work has demonstrated that CD11b agonism via LA1 transiently enhances integrin-mediated adhesion that limits immune cell transmigration and tissue infiltration. CD11b agonism also suppresses TLR-driven inflammatory signaling and myeloid cell activation. To evaluate its efficacy in vivo, we utilized pre-clinical Parkinson's disease model by stereotaxically delivering AAV2-SYN to induce -synuclein overexpression in the murine midbrain. Mice were treated with oral LA1 for four or eight weeks and analyzed. LA1 treatment significantly reduced microglial activation and decreased brain infiltration of peripheral immune cells, thereby attenuating -synuclein-induced neuroinflammation. These findings suggest that CD11b agonism may offer a dual-action therapeutic approach in Parkinson's disease by dampening pro-inflammatory responses by central and peripheral myeloid cells.

PU.1-driven enrichment enables microglia profiling from frozen brain tissue using the high-throughput Smart-seq3xpress method
Single-cell transcriptomics has revealed the central role of microglia in brain development, homeostasis, and disease, particularly in the context of neuroinflammation. While single-cell RNA-sequencing enables targeted microglial analysis from fresh tissue, studying these cells in cryopreserved or archival samples remains challenging due to the lack of protocols for their specific enrichment. We introduce a method for the selective isolation of microglial nuclei from fresh-frozen brain tissue using the transcription factor PU.1 as a nuclear marker. To stabilize PU.1 for reliable detection, a brief formaldehyde fixation step is applied. The protocol is fully compatible with Smart-seq3xpress, a high-sensitivity, full-length transcriptomic method offering isoform- and allele-level resolution, making the workflow scalable and cost-efficient. We benchmarked the method in a mouse model of ischemic stroke, evaluating both technical performance and its ability to capture biologically meaningful microglial states. Compared to standard single-nucleus protocols, our approach yielded higher gene and UMI counts and a greater proportion of coding reads. Transcriptomic profiles closely matched those from whole-cell RNA- sequencing including the detection of activation markers and diverse microglial subpopulations. This approach addresses key limitations of single-nucleus RNA - sequencing and opens new possibilities for studying microglial states in cryopreserved and archival brain tissue, broadening access to cellular insights in both basic and translational research. Key words: Enrichment, Frozen tissue, Microglia, PU.1, Smart-seq3xpress, single-nucleus RNA - sequencing, Stroke, Transcriptomics

BIN1 expression in the presynaptic compartment leads to isoform-specific synaptotoxicity
Alzheimer's disease (AD) is characterized by a strong genetic predisposition and by an early loss of synaptic connectivity that strongly correlates with cognitive deficit. Some genetic determinants could contribute to synapse frailty toward AD pathology. However, the role of genetic determinants in AD pathogenesis remains poorly understood at the synaptic level. Here, we show that the expression of an isoform of the major AD susceptibility gene BIN1 in the presynaptic compartment results in synaptic loss. Using electrophysiology, we observed an early loss of synaptic transmission upon BIN1 isoform 1 (BIN1iso1) expression in Drosophila retinal photoreceptor neurons. This was not observed for the other human BIN1 isoforms tested, isoform 8 and isoform 9. Structural analysis of photoreceptor neuron synapses shows a strong accumulation of abnormally large vesicles in the presynaptic compartment, reminiscent of this same isoform-induced endosome defects in cell bodies. In addition, the expression of BIN1iso1 in motoneurons of the Drosophila neuromuscular junction alters the morphology of synaptic boutons, with a greater number and a smaller size of synaptic boutons, and the appearance of satellite boutons. As opposed to endosomal defects in cell body, modulating the Rab11 recycling endosome regulator did not prevent BIN1iso1 synaptotoxicity. To test if synaptic deficits are conserved in a mammalian model and to assert a presynaptic vs postsynaptic role for BIN1, we used rat primary neurons cultured in microfluidic devices that restrict gene expression modulation in particular neuron populations. We found a loss of synaptic connectivity only when expressing BIN1iso1 in the presynaptic compartment, which was confirmed by microelectrode array analysis. Together, our results suggest that BIN1 expression in the presynaptic terminal, but not the postsynaptic terminal leads to an isoform-specific, deleterious effect on synaptic integrity. BIN1 synaptotoxicity could contribute to the synapse loss observed early in AD. This supports the idea that genetic determinants could make synapses prone to failure in AD.

Inverse expression of Ten3 and Lphn2 across the developing mouse brain reveals a global strategy for circuit assembly
Precise wiring of neural circuits requires molecular strategies that ensure accurate target selection across diverse brain regions. Here, we identify inverse expression between a ligand-receptor pair, Teneurin-3 (Ten3) and Latrophilin-2 (Lphn2), throughout the developing mouse brain. Ten3 and Lphn2 exhibit inverse expression gradients along a retinotopic axis orthogonal to the ephrin-A and EphA gradients; along the tonotopic axis across multiple brainstem auditory nuclei; and along the dorsomedial-ventrolateral axis in striatum and pallidum. Their inverse expression also creates discrete domains of cerebellar Purkinje cells and cerebellar nuclei along the mediolateral axis. Using conditional tag mice, we show that inverse Ten3 and Lphn2 expression patterns predict connectivity, following a 'Ten3 [->] Ten3, Lphn2 [->] Lphn2' rule in all above circuits. We further demonstrate a functional role for Lphn2 in executing this rule in Purkinje cells [->] cerebellar nuclei projection. Our findings reveal a global strategy of coordinating gene expression of key wiring molecules with circuit connectivity across the developing brain.

Distributed theta networks support the control of working memory: Evidence from scalp and intracranial EEG
We combined scalp EEG and intracranial EEG (iEEG) to identify spectral and network-level signatures of executive control during a delayed match-to-sample task working memory task. To isolate executive processes, we contrasted test and sample phases, matched in perceptual input but differing in cognitive demand. Scalp EEG revealed increased frontal midline theta event-related spectral perturbations (ERSPs), dynamic increases and decreases in posterior theta-alpha ERSPs, and decreased central alpha-beta ERSPs during the test phase. These local spectral changes were accompanied by enhanced frontoposterior theta phase synchrony and network hub strength, predicting higher behavioral accuracy. Using a novel cross-modal scalp EEG-iEEG ERSP similarity approach, we localized the sources of scalp-derived frontal midline, posterior, and central control effects to medial frontal, parietal, temporal, and occipital regions. Our results integrate power and connectivity measures across scalp and iEEG, linking local spectral fluctuations to broader network organization. Together, they support a model in which executive control emerges from flexible, temporally precise coordination between medial frontal control hubs and posterior representational systems.

An astrocytic AMPK clock drives circadian behaviour
Circadian clocks coordinate behaviour and physiology with daily cycles of light and nutrient availability, yet how metabolic signals tune brain timing remains unclear. Astrocytes integrate metabolic and hormonal cues and sustain cell-autonomous rhythms, implicating them as candidate links between energy state and central circadian control. Here we show that AMP-activated protein kinase (AMPK) in hypothalamic astrocytes exhibits intrinsic, calcium-dependent rhythmicity that persists under constant darkness and without feeding cues. This glial rhythm sustains time-of-day phosphorylation programmes in the hypothalamus and stabilises the clock protein PER2 via phosphorylation at a conserved serine residue, thereby linking metabolic state to period control beyond the canonical transcription-translation feedback loops. In the ventromedial hypothalamus, astrocytic AMPK-PER2 signalling is required for food-anticipatory activity, identifying a glial node within the food-entrainable timing system. Disrupting astrocytic AMPK rhythmicity alters circadian behaviour and energy homeostasis and shortens lifespan in a sex-dependent manner. These findings recast AMPK as a metabolically adaptive glial timekeeper that connects calcium signalling and phosphorylation rhythms to behaviour and metabolism. They also reveal a phosphorylation-based timing layer in central metabolic circuits, with implications for circadian-metabolic misalignment in contexts such as shift work and metabolic disorders.

Teneurin-3 and latrophilin-2 are required for somatotopic map formation and somatosensory topognosis
Somatotopy is a recurring organizational feature of the somatosensory system where adjacent neurons and their connections represent adjacent regions of the body. The molecular mechanisms governing the formation of such "body maps" remain largely unknown. Here we demonstrate that the cell surface proteins teneurin-3 and latrophilin-2 are expressed in opposing gradients in multiple somatotopic maps in the mouse, including within the dorsal horn of the spinal cord. Genetic manipulation of these proteins in spinal dorsal horn or sensory neurons distorts the somatotopy of neuronal connections and impairs accurate localisation of a noxious stimulus on the surface of the body. Our work provides the foundation for a molecular model of somatotopic map formation and insights into their function in localisation of somatosensory stimuli or topognosis.

Exploring Cerebellar Hippocampal Dynamics in Temporal Lobe Epilepsy: A Multivariable Synthetic Modeling Study of Purkinje Cell Degeneration and Stimulation Timing
Objective: To determine whether Purkinje cell degeneration precedes or follows seizure onset in temporal lobe epilepsy (TLE), identify shared cerebello-hippocampal pathways, and evaluate the influence of stimulation timing on modeled seizure outcomes. Methods: We constructed a 50-variable evidence model integrating structural, molecular, and circuit-level data from published literature. This framework generated a PASS-validated synthetic cohort of 10,000 virtual subjects, with validation details in the Appendix. Analyses employed causal inference with inverse probability of treatment weighting (IPTW), mediation analysis, factorial ANOVA, and the Two One-Sided Test [TOST] for equivalence. The model predictive fit was deliberately modest (RMSE = 0.499; R square = -0.010), focusing on causal insights rather than precise prediction. Evaluations were stratified by timing and circuit integrity. Results: Causal analysis revealed a weak, nonsignificant direct effect of Purkinje cell density on seizure burden (ATE = +0.0045, 95% CI: -0.0053 to +0.0143) [Table 1, row 1]. Mediation via GABAergic pathways was negligible. Early stimulation ([≤]4 days post-onset) significantly reduced seizure burden (p = 0.045, mean Delta; = -0.020), with a timing x integrity interaction [Table 1, row 3]. Factorial ANOVA confirmed this interaction (F = 3.30, p = 0.019, partial eta square= 0.001), with Tukey HSD emphasizing timing role. TOST with a +/-0.015 margin did not confirm equivalence for Purkinje effects (P1; = 0.0019, ;P2;= 0.136), suggesting minimal impact. Sensitivity and perturbation tests across 10,000-subject cohorts ensured robustness. Interpretation: This model suggests cerebellar stimulation mitigates seizure burden through timely intervention rather than Purkinje integrity. Recent studies support cerebellar changes in TLE and rTMS-induced vermis volume increases linked to seizure reduction.Trials of transcranial alternating current stimulation in refractory TLE align with our findings. Results from synthetic data propose translational validation. Conclusion: Optimizing stimulation timing offers a testable strategy to modulate hippocampal excitability in TLE, independent of Purkinje status, highlighting synthetic model utility in exploring dynamic interventions.

Ten3-Lphn2-mediated target selection across the extended hippocampal network demonstrates a repeated strategy for circuit assembly
How do a limited number of wiring molecules specify trillions of connections in developing brains? We previously found that inverse expression of a ligand-receptor pair, Teneurin-3 (Ten3) and Latrophilin-2 (Lphn2) in CA1 and subiculum instructs CA1[->]subiculum target selection through Ten3-Ten3 homophilic attraction and Ten3-Lphn2 heterophilic reciprocal repulsion. Here, we leveraged conditional knockouts to systematically demonstrate that these mechanisms generalize to extended hippocampal connections, including entorhinal cortex and hypothalamus. Cooperation between attraction and repulsion differs depending on the order developing axons encounter the attractant and repellent subfields. Strikingly, Ten3 and Lphn2 can serve both as ligands for incoming axons and receptors for their own target selection, within the same neuron; Ten3 can be repulsive or attractive as ligand or receptor. Thus, multifunctionality and repeated use, together with the recurrent circuit motifs prevalent in the brain, enable one ligand-receptor pair to instruct target selection of many more neurons.

Striatal neuron excitability is regulated by huntingtin in the adult brain
Huntington disease (HD) is a hereditary neurodegenerative disease that typically presents during midlife and is characterized by a combination of motor, cognitive and psychiatric symptoms. HD is fatal and arises from a mutation in the huntingtin (HTT) gene, which results in decreased neuronal health followed by brain atrophy, with spiny projection neurons (SPNs) of the striatum being especially vulnerable to degeneration. HTT loss-of-function, caused by haploinsufficiency of the wild type HTT gene (wtHTT), is an important feature of HD pathophysiology that has previously been understudied compared to mutant HTT gain-of-function mechanisms. wtHTT is essential for nervous system development and functions as a scaffolding protein to support many vital cellular functions including axonal transport, autophagy and synaptic plasticity. Here, we examined the consequences of wtHTT deletion in the adult striatum by conditionally inactivating wtHTT in 2-4 month old male and female Httfl/fl mice. wtHTT loss of function in mature SPNs decreased intrinsic neuronal excitability and produced a neuroinflammatory response in these mice, while tissue organization, spine morphology and motor behaviour remained unaffected. Results presented here provide additional evidence that wtHTT is vital for maintaining neuronal health in the adult brain and highlight some potential adverse consequences of non-selective HTT-lowering for the treatment of HD.

Pharmacological Depletion of Retinal Mononuclear Phagocytes is Neuroprotective in a Mouse Model of Mitochondrial Optic Neuropathy
Purpose: The Vglut2-Cre;ndufs4loxP/loxP mouse strain with retinal ganglion cell (RGC)-specific mitochondrial complex I dysfunction develops severe RGC degeneration by postnatal day 90 (P90), with accompanying retinal mononuclear phagocyte (MNP) accumulation. We have reported that continuous exposure to hypoxia partially rescues RGC death in these mice, with minimal effect on MNP abundance. We hypothesized that pharmacological depletion of MNPs with the colony-stimulating factor-1 receptor inhibitor pexidartinib would enhance RGC neuroprotection by hypoxia. Methods: Iba1+ retinal MNP depletion was assessed in C57Bl/6J mice fed control or pexidartinib-infused chow beginning at P25. Subsequently, Vglut2-Cre;ndufs4loxP/loxP mice and control littermates were raised under normoxia or hypoxia and fed control or pexidartinib chow from P25 to P90. The neuroprotective effect of pexidartinib and hypoxia alone and in combination was assessed by quantifying RGC soma and axon survival in retinal flat mounts and optic nerve cross sections. Results: Pexidartinib completely depleted retinal MNPs within one week of treatment. Untreated Vglut2-Cre;ndufs4loxP/loxP mice exhibited the expected ~50% reduction of RGC soma and axon survival at P90 (p<0.0001 for both). Hypoxia or pexidartinib monotherapy each reduced RGC degeneration by more than one-half, while their combination resulted in complete RGC neuroprotection (p<0.001 for all three treatments). Normal myelination patterns were restored in mice receiving dual therapy. Conclusions: Pexidartinib effectively depletes retinal MNPs and is neuroprotective in the setting of severe RGC mitochondrial dysfunction. This therapeutic effect is additive to that of hypoxia. Combating retinal neuro-inflammation may therefore be a useful adjunct therapy in mitochondrial optic neuropathies like Leber hereditary optic neuropathy.

Analysis of human visual experience data
Exposure to the optical environment, often referred to as visual experience, profoundly influences human physiology and behavior across multiple time scales. In controlled laboratory settings, stimuli can be held constant or manipulated parametrically. However, such exposures rarely replicate real-world conditions, which are inherently complex and dynamic, generating high-dimensional datasets that demand rigorous and flexible analysis strategies. This tutorial presents an analysis pipeline for visual experience datasets, with a focus on reproducible workflows for human chronobiology and myopia research. Light exposure and its retinal encoding affect human physiology and behavior across multiple time scales. Here we provide step-by-step instructions for importing, visualizing, and processing viewing distance and light exposure data using the open-source R package LightLogR. This includes time-series analyses for working distance, biologically relevant light metrics, and spectral characteristics. By leveraging a modular approach, the tutorial supports researchers in building flexible and robust pipelines that accommodate diverse experimental paradigms and measurement systems.

Characterizing Surround Suppression with Dynamic Natural Scenes
Surround suppression refers to the reduction in perceptual sensitivity to a central stimulus caused by its surrounding context. Previous studies have examined this phenomenon mainly with simple stimuli varying only in low-level visual features, leaving it unclear whether the same principles apply to natural scenes. To address this, we investigated surround suppression in complex and dynamic scenes by systematically manipulating categorical similarity and motion congruence between the center and surrounding scenes. Categorical similarity was examined across four levels: identical exemplars, different exemplars of the same basic-level category, different basic-level categories, and different superordinate categories. Motion direction was manipulated by center and surround drifting either in the same or opposite directions. In two experiments, we measured contrast sensitivity for the center scene during a categorization task. We found that the suppression increased as the categorical similarity between the center and the surround decreased, with the strongest suppression observed for different superordinate categories. This contrasts with results for simple stimuli, where increasing center-surround similarity increases suppression. Yet, consistent with the findings from simple stimuli, suppression was stronger when the center and surround moved in the same direction. These findings show that contextual modulation in natural vision is governed not only by low-level feature similarity but also by high-level categorical structure. Context-dependent suppression may therefore help the visual system prioritize coherent, task-relevant information while filtering incongruent input.

Mobile Eye Tracking in the Real World: Best Practices
As research on human behavior, such as spatial navigation, increasingly adopts naturalistic settings, establishing best practices for such experiments becomes essential. While virtual reality (VR) offers a bridge between laboratory control and real-world complexity, it does not fully capture the experiential richness of real-world environments. Here, we present a demonstration of a mobile eye-tracking study conducted in a large-scale, outdoor urban environment, featuring unconstrained, long-duration free exploration and outside-pointing tasks. Using the city of Limassol, Cyprus as our testbed, we showcase the feasibility of collecting high-quality mobile eye-tracking, head orientation, and GPS data "in the wild," capturing a wide range of natural behavior with minimal experimental constraints. Based on this experience, we provide a set of best practices tailored to the logistical and methodological challenges posed by complex, real-world urban settings, challenges unlikely to arise in traditional indoor or highly controlled environments. While these recommendations have general relevance, we exemplify them in the context of spatial navigation research. By establishing methodological standards for studies at this scale, we aim to encourage and inform future research into naturalistic human behavior outside the laboratory.

DynVision: A Toolbox for Biologically Plausible Recurrent Convolutional Networks
Convolutional Neural Networks (CNNs) have demonstrated remarkable success in image recognition and exhibit conceptual similarities to the primate ventral visual pathway. Adding recurrence opens the door to exploring temporal dynamics and investigating mechanisms underlying recognition robustness, attentional modulation, and rhythmic perception phenomena. However, modeling spatiotemporal dynamics of biological vision using CNN-based architectures remains challenging. Incorporating functionally beneficial recurrence, capturing biologically plausible temporal phenomena such as adaptation and subadditive temporal summation, and maintaining topographic organization aligned with cortical structure require significant computational considerations. Although recent advances have incorporated neurobiological constraints, the field lacks accessible tools for efficiently integrating, testing, and comparing these approaches. Here, we introduce DynVision, a modular toolbox for constructing and evaluating recurrent convolutional neural networks (RCNNs) with biologically inspired dynamics. Our approach facilitates the incorporation of key visual cortex properties, including realistic recurrent architectures, activity evolution governed by dynamical systems equations, and structured connectivity reflecting cortical arrangements, while maintaining computational efficiency. We demonstrate the framework's utility through systematic analysis of emergent neural dynamics, highlighting how different biologically motivated modifications shape scientifically-relevant response patterns. Code can be found at: https://github.com/Lindsay-Lab/DynVision/

A Coupling Model of Transcranial Magnetic Stimulation Induced Electric Fields to Neural State Variables
Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique used to modulate neural activity, with applications in clinical treatment, diagnostics, and neuroscientific research. TMS targeting the human primary motor cortex (M1) is well studied, aided by experimental readouts from the cerebral cortex, the spinal cord, and activated muscle targets. One key readout is a series of pulses that descend the spinal cord following TMS, called DI-waves. These reflect the output of M1 to the spinal cord and are influenced by TMS parameters such as orientation, strength, and waveform. Previous modeling studies have deployed numerous strategies to explain DI-wave generation, but generally approximate TMS inputs as semi-arbitrary current or synaptic inputs. A consistent missing piece to these models is a biophysically motivated coupling between TMS and the neural states of cells and cell populations. This study aims to leverage cable simulations of realistic neuron morphologies to couple TMS induced electric fields to average state variables of cortical cell populations. This coupling model quantifies the spatial-temporal activation function of directly stimulated axonal fibers and the average input current that downstream cells receive due to synaptic inputs from directly stimulated cells. An example M1 cortical circuit is studied, in which TMS stimulates layer 2/3 excitatory and inhibitory neurons that project synapses onto layer 5 corticospinal neurons. Results indicate that TMS induces unique directionally sensitive distributions of synaptic outputs in time and space for each cell type. Directional and dosage sensitivity carries forward to the dendritic current flowing into layer 5 cells. Ultimately, the coupling model provides a novel architecture to translate electric fields from TMS into activation functions that alter neural states and serve as inputs to cortical circuit modeling. The study of other brain regions is achievable through an alternate choice of cell morphologies, cell locations, and circuit design.

Your Emotions, My Brain: Generalizable Neural Signatures of Emotional Memory Reactivation During Sleep
Reactivation in sleep alters the structure of memories and can potentially be used to restructure upsetting representations. Reactivation can be triggered with auditory cues and then detected using machine learning and electroencephalography (EEG), but can we also detect the emotionality of reactivated memories? We examined this by presenting auditory cues that had been associated with negative or neutral stimuli in wake during subsequent NREM sleep and training a classifier to detect the emotionality of subsequent EEG responses. We were able to detect the reinstatement of emotionality 0.4-0.6 seconds after cue presentation. Importantly, we used a between-participant machine learning pipeline to identify shared neural signatures of emotionality across individuals without fine-tuning the model on testing participants. This approach eliminates the need for individualized wake localizer sessions, establishing a methodologically efficient framework for investigating emotional processing during sleep. Detection of emotional reactivation in sleep will help us to understand how such reactivation impacts upon the emotionality of the memories in the long term, potentially facilitating development of treatments for PTSD and depression through memory restructuring in sleep.

Normative neural and physiological correlates of parent-child observational threat extinction
The dyadic relationship between a parent and child is a critical facilitator of social learning, particularly in the management of fear. Vicarious extinction, the process of learning by observing a parent extinguish learned threat responses, holds critical translational potential in understanding adolescent psychopathology involving aberrant threat responses. However, normative biological profiles of vicarious extinction have yet to be uncovered. Here, a community sample of 97 parent-child dyads, enriched for trauma-exposure, completed a validated vicarious extinction paradigm. Youth completed all phases during functional magnetic resonance imaging, while caregivers simultaneously completed the behavioral task. Linear models interrogating normative behavioral, physiological, and neural correlates of acquisition and direct and vicarious extinction, controlled for trauma and symptom severity. The degree of parent-child autonomic synchrony was used to predict the strength of extinction learning. Youth behavioral and skin conductance response markers suggest successful threat acquisition and direct and vicarious extinction. Autonomic arousal during active vicarious extinction learning processes was significantly associated with the strength of parent-child synchrony. Neural activation analyses reveal patterns of early encoding of threat and safety discrimination that were reactivated during later threat reinstatement. Finally, results corroborate and expand known models of direct and vicarious extinction, respectively involving the ventromedial and ventrolateral prefrontal cortex. Altogether, this data confirms that youth can directly and vicariously modify learned threat associations with distinct neurobiological profiles. This delineation of vicarious extinction neural circuitry within a normative population is pivotal for understanding how these processes may be altered by the environment and/or psychopathology during adolescence.

Tactile Pressure Evokes a Biphasic BOLD Response in Ipsilateral Primary Somatosensory Cortex
Tactile perception is fundamental to how we engage with and interpret our surroundings. While the contralateral primary somatosensory cortex (S1) is thought to be generally responsible for processing tactile information, simultaneous responses in the ipsilateral hemisphere have been observed. This work aims to characterize the blood-oxygen-level-dependent (BOLD) response pattern of ipsilateral S1 to unilateral tactile stimuli. In this study, tactile stimuli were applied using a custom pneumatically actuated stimulator designed and built in house (KalantaryArdebily et al., 2024). Three stimulus force levels were applied in an event-related design. As expected we observed an apparent difference in BOLD responses between the contralateral and ipsilateral hemispheres. We found differing response patterns between the Brodmann's areas (BA) within ipsilateral S1. Ipsilateral BA2 had a positive BOLD response similar to that of the contralateral hemisphere. In contrast, ipsilateral BA1 and BA3b appeared to have a biphasic response. That is, those regions had an initial negative response, followed by a secondary positive one. Using multi-echo analysis, we verified that this biphasic response pattern is BOLD-related. In addition, the secondary (positive) phase was more sensitive to tactile stimulus force than the initial "negative" BOLD phase. The ipsilateral BA1 and BA3b responses support a previous hypothesis of bilateral sensory gating (Blatow et al., 2007; Chung et al., 2014; Hamalainen et al., 2000; Kastrup et al., 2008; Klingner et al., 2016; Schafer et al., 2012; Tame et al., 2015). This study extends previous research reporting negative responses in ipsilateral S1, suggesting that the response is BOLD-related, biphasic, and that the previously overlooked secondary positive phase is actually more sensitive to stimulus intensity.

The Social Switchboard: Context and Rank Shapes Behavioural and Neural Responses During Macaque Decision-Making
Social interactions shape many of our most ethologically relevant decisions and require considerable cognitive sophistication. Factors such as immediate needs, social bonds, hierarchical status, and reciprocity norms impact decision-making. Yet most laboratory paradigms examine individuals in isolation. We developed a face-to-face cognitive testing platform using a transparent touchscreen that allowed pairs of adult male Macaca fascicularis (n = 6) with established dominance relationships to perform a decision-making task across six social contexts: audience, co-action, envy, cooperation, competition, and altruism. We recorded eye movements simultaneously from both subjects (gaze position and pupil diameter), synchronised behavioural video, and task performance. Across social contexts, macaques performed better in the presence of a conspecific than when tested alone, but performance declined under altruistic and competitive conditions. Dominance substantially modulated motivation: dominant subjects were less willing to engage when rewards were shared (envy), when only the partner was rewarded (altruism), or when contingent action with a subordinate was required (cooperation). Eye-tracking revealed greater pre-choice arousal and social attention during social sessions, indexed by larger pupils, longer fixations on the partner's face, and more saccades before (but not during or after) choices. Pupil dilation was larger in dyads where both individuals were dominant than in dyads where one was subordinate. Finally, noninvasive functional near-infrared spectroscopy (fNIRS) showed increased cortical engagement relative to baseline in audience, altruism, competition, and cooperation conditions. These findings demonstrate that social context and hierarchical dominance systematically shape choices, attentional allocation, autonomic arousal, and cortical engagement in macaques, and provide a tractable platform for further dissecting the neural bases of contextual social decision-making.

Structural connectome architecture and biological vulnerability shape cortical atrophy in cocaine use disorder
Cocaine use disorder (CUD) is prevalent and characterized by widespread gray matter atrophy across the cerebral cortex. However, it remains unclear whether and how connectome-based circuits and biological features shape these structural abnormalities. Here, we show that CUD-associated regional atrophy is constrained by the white matter (WM) structural connectome. Along these WM pathways, regions that share similar haemodynamic activity and molecular profiles are more likely to exhibit analogous atrophy patterns. By integrating the structural connectome with these multiple connectivity blueprints, we subsequently identify CUD epicenters and reveal that the prefrontal and visual cortices serve as core systems. Furthermore, we link these epicenters to cortical gene expression patterns and delineate CUD-related transcriptomic enrichment in biological processes, including inter-neuronal communication, synaptic function and neural homeostasis. Finally, we demonstrate that the spatial distribution of these epicenters correlates with cocaine craving-response maps derived from repeated transcranial magnetic stimulation and can track individual variations in clinical behavioural representations, suggesting their potential as key targets for therapeutic intervention. Together, our findings establish a structurally constrained framework for the spread of pathology underlying cortical atrophy in CUD, where initial perturbations propagate via structural connectome pathways to vulnerable regions shaped by neural activity and molecular landscapes.